This invention relates to a class of aromatic compounds which are blockers of calcium channels. The invention also relates to pharmaceutical compositions, methods of blocking calcium channels, kits and methods of treatment using the class of compounds described herein, as well as intermediate compounds useful in the preparation of the compounds.
Calcium channel blockers are a chemically diverse class of compounds having important therapeutic value in the control of a variety of diseases including several cardiovascular disorders, such as hypertension, angina, and cardiac arrhythmias (Fleckenstein, Cir. Res. v. 52, (suppl. 1), p.13-16 (1983); Fleckenstein, Experimental Facts and Therapeutic Prospects, John Wiley, New York (1983); McCall, D., Curr Pract Cardiol, v. 10, p. 1-11 (1985)).
Calcium channel blockers are a heterogenous group of drugs that prevent or slow the entry of calcium into cells by regulating cellular calcium channels. (Remington, The Science and Practice of Pharmacy, Nineteenth Edition, Mack Publishing Company, Eaton, Pa., p.963 (1995)). The regulation of calcium entry into the cells of the cardiovascular system is of paramount importance to the proper functioning of this system. Cardiac and vascular smooth muscle cells have calcium channels within the cell membrane. Calcium influx through these channels initiates a process of electromechanical coupling which ultimately leads to muscle contraction. The ability to regulate the entry of calcium into cardiac and vascular smooth muscle cells is a powerful therapeutic approach in the treatment of angina and hypertension respectively. Likewise, blocking calcium influx into cardiac tissues and conduction systems provides a useful approach to control certain types of arrhythmia.
Calcium channel blockers are also believed to be useful in the treatment of other disorders in which the regulation of calcium plays a role in normal hemostasis. Such disorders include, for example, pulmonary hypertension, peripheral vascular disease, mild congestive heart failure, hypertrophic subaortic stenosis, protection against ischemic injury, stroke, migraine, tumor resistance to anti-neoplastic drugs, achalasia, esophageal spasms, bronchial asthma, premature labor, dysmenorrhea, and enhancement of success in renal transplantation. (Remington, The Science and Practice of Pharmacy, Nineteenth Edition, Mack Publishing Company, Eaton, Pa., p.963 (1995)).
Most of the currently available calcium channel blockers belong to one of three major chemical groups of drugs, the dihydropyridines, such as nifedipine, the phenyl alkyl amines, such as verapamil, and the benzothiazepines such as diltiazem. While the structure activity relationships (SAR) of the dihydropyridines and the phenyl alkyl amines are well defined and extensively studied, very limited information is available on the SAR of benzothiazepines such as diltiazem. Diltiazem is a chiral molecule, with a seven membered fused-ring system, having a thiazepine, which is fused with a benzene ring. The structure is further characterized by three key functional groups, a 4-methoxybenzyl substituent at position xe2x80x9c2xe2x80x9d; an actoxy ester at position xe2x80x9c3xe2x80x9d; and positions xe2x80x9c4xe2x80x9d and xe2x80x9c5xe2x80x9d forming an amide function with N,N-dimethylaminoethyl substitution at the amide nitrogen. Scientists at central research laboratory at Osaka, Japan, synthesized a series of potent calcium channel blockers in which the seven membered ring of diltiazem was replaced with 6- and 5-membered fused-ring systems. These two new classes of calcium channel blockers, the benzothiazine and benzothiazole respectively (Yamamoto, K., J. Med. Chem., v. 31, p. 919-930(1988); Fujita, M., J. Med. Chem., v.33, p. 1898-1905 (1990)) demonstrated potent calcium channel blocking activity. Some of these compounds even demonstrated more tissue selectivity toward calcium channels in blood vessels.
A new family of calcium channel blockers, which are defined by the structures set forth below, have been identified according to the invention. The members of the new family of compounds constitute a new class of calcium channel blockers which is not encompassed by any of the three known classes of calcium channel blockers, the dihydropyridines, the phenyl alkyl amines, or the benzothiazepines. Of the three known classes the compounds of the invention are most structurally similar to the benzothiazepine class of calcium channel blockers, which have the following structural formula. 
Prior to the instant invention it was believed that the fused ring structure of the benzothiazepines was essential for the calcium channel blocking activity of these compounds. Applicants, however, have surprisingly discovered that compounds having the basic central atomic structure of the benzothiazepines but lacking the fused ring structure have calcium channel blocking activity and actually demonstrate comparable anti-hypertensive activity to traditional benzothiazepines such as diltiazem.
In one aspect the invention is a composition of a compound having the following structural formula:
Ar1xe2x80x94Xxe2x80x94Ar2
wherein Ar2 is an aryl group or a heteroaryl group, wherein the heteroaryl is a ring having 5, 6, or 7 atoms, and wherein at least one atom of the heteroaryl is selected from the group consisting of a sulfur, a nitrogen, and an oxygen atom, and which is substituted with R1, R2, R3, R4, and R5;
wherein Ar1 is an aryl group or a heteroaryl group,wherein the heteroaryl is a ring having 5, 6, or 7 atoms, and wherein at least one atom of the heteroaryl is selected from the group consisting of a sulfur, a nitrogen, and an oxygen atom, and which is substituted with R6, R7, R8, R9, and R10;
wherein R1, R2, R3, R4, R5, R7, R8, R9, and R10 independent of one another, are selected from the group consisting of xe2x80x94H, halogen, piperonyl, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C1-C6)alkoxy xe2x80x94CN, xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, xe2x80x94NO2, xe2x80x94NRxe2x80x2Rxe2x80x2, amino acid, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(S)Rxe2x80x2, xe2x80x94C(O)ORxe2x80x2, xe2x80x94C(S)ORxe2x80x2, xe2x80x94C(O)SR, xe2x80x94C(S)SRxe2x80x2, xe2x80x94C(O)N(Rxe2x80x2)2, xe2x80x94C(O)C(O)Rxe2x80x2, xe2x80x94C(S)C(O)Rxe2x80x2, xe2x80x94C(O)C(S)Rxe2x80x2, xe2x80x94C(S)C(S)Rxe2x80x2, xe2x80x94C(O)C(O)ORxe2x80x2, xe2x80x94C(S)C(O)ORxe2x80x2, xe2x80x94C(O)C(S)ORxe2x80x2, xe2x80x94C(O)C(O)SRxe2x80x2, xe2x80x94C(S)C(S)ORxe2x80x2, xe2x80x94C(S)C(O)SRxe2x80x2, xe2x80x94C(O)C(S)SRxe2x80x2, xe2x80x94C(S)C(S)SRxe2x80x2, xe2x80x94C(O)C(O)N(Rxe2x80x2)2, xe2x80x94C(S)C(O)N(Rxe2x80x2)2, xe2x80x94C(O)C(S)N(Rxe2x80x2)2, or xe2x80x94C(S)C(S)N(Rxe2x80x2)2;
wherein R6 is in the ortho position and is selected from the group consisting of xe2x80x94COxe2x80x94NHxe2x80x94(CH2)2-5NH2, xe2x80x94COxe2x80x94NHxe2x80x94(CH2)2-5NHxe2x80x94(CH2)zxe2x80x94H, xe2x80x94COxe2x80x94NH(CH2)2-5NR15(CH2)zxe2x80x94H, xe2x80x94COxe2x80x94Rxe2x80x2, xe2x80x94COxe2x80x94ORxe2x80x2, xe2x80x94COxe2x80x94SRxe2x80x2, xe2x80x94COxe2x80x94N(Rxe2x80x2)2, xe2x80x94COxe2x80x94COxe2x80x94Rxe2x80x2, xe2x80x94COxe2x80x94CSxe2x80x94Rxe2x80x2, xe2x80x94COxe2x80x94COxe2x80x94ORxe2x80x2, xe2x80x94COxe2x80x94CSxe2x80x94ORxe2x80x2, xe2x80x94COxe2x80x94COxe2x80x94SRxe2x80x2, xe2x80x94COxe2x80x94CSxe2x80x94SRxe2x80x2, xe2x80x94COxe2x80x94COxe2x80x94N(Rxe2x80x2)2, xe2x80x94COxe2x80x94CSxe2x80x94N(Rxe2x80x2)2, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(CH2)2-5NH2, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(CH2)2-5NHxe2x80x94(CH2)zxe2x80x94H, xe2x80x94NHxe2x80x94COxe2x80x94NH(CH2)2-5NR15(CH2)zxe2x80x94H, xe2x80x94NHxe2x80x94COxe2x80x94Rxe2x80x2, xe2x80x94NHxe2x80x94COxe2x80x94ORxe2x80x2, xe2x80x94NHxe2x80x94COxe2x80x94SRxe2x80x2, xe2x80x94NHxe2x80x94COxe2x80x94NO2, xe2x80x94NHxe2x80x94COxe2x80x94N(Rxe2x80x2)2, xe2x80x94NHxe2x80x94COxe2x80x94COxe2x80x94Rxe2x80x2, xe2x80x94NHxe2x80x94COxe2x80x94CSxe2x80x94Rxe2x80x2, xe2x80x94NHxe2x80x94COxe2x80x94COxe2x80x94ORxe2x80x2, xe2x80x94NHxe2x80x94COxe2x80x94CSxe2x80x94ORxe2x80x2, xe2x80x94NHxe2x80x94COxe2x80x94COxe2x80x94SRxe2x80x2, xe2x80x94NHxe2x80x94COxe2x80x94CSxe2x80x94SRxe2x80x2, xe2x80x94NHxe2x80x94COxe2x80x94COxe2x80x94N(Rxe2x80x2)2, and xe2x80x94NHxe2x80x94COxe2x80x94CSxe2x80x94N(Rxe2x80x2)2,
wherein each Rxe2x80x2 is (CH2)zxe2x80x94NRxe2x80x3Rxe2x80x3 and wherein Rxe2x80x3 is independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkynyl, (C6-C20)aryl, (C6-C20)substituted aryl, (C6-C26)alkaryl, substituted (C6-C26)alkaryl, and (C5-C7)heteroaryl wherein at least one atom of the heteroaryl is selected from the group consisting of a sulfur, a nitrogen, or an oxygen atom, wherein the aryl and alkaryl substituents are each independently selected from the group consisting of hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl and trihalomethyl;
wherein z is 1-6;
wherein R15 is selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, and (C1-C6)alkoxy;
wherein X is a group having the following formula;
xe2x80x94(CH2)mxe2x80x94Yxe2x80x94(CH2)nxe2x80x94
wherein Y is selected from the group consisting of S, N, and O; and
wherein m and n, independent of one another, are integers of 0-5.
In a preferred embodiment the compound has the general structural formula: 
wherein each of the R groups is as defined above.
In another embodiment the compound has the general structural formula: 
wherein R11 is selected from the group consisting of xe2x80x94NHxe2x80x94CH2CH2NH2, xe2x80x94NHxe2x80x94CH2CH2Nxe2x80x94(CH2)zxe2x80x94H, xe2x80x94N.(CH2)2NR15.(CH2)2, xe2x80x94Rxe2x80x2, xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, xe2x80x94NO2, xe2x80x94N(Rxe2x80x2)2, xe2x80x94COxe2x80x94Rxe2x80x2, xe2x80x94CSxe2x80x94Rxe2x80x2, xe2x80x94COxe2x80x94ORxe2x80x2, xe2x80x94CSxe2x80x94ORxe2x80x2, xe2x80x94COxe2x80x94SRxe2x80x2, xe2x80x94CSxe2x80x94SRxe2x80x2, xe2x80x94COxe2x80x94N(Rxe2x80x2)2, and xe2x80x94CSxe2x80x94N(Rxe2x80x2)2 and wherein R1-R5 and R7-R10 are as described above.
In yet another embodiment R11 is selected from the group consisting of xe2x80x94NHxe2x80x94CH2CH2NH2 and xe2x80x94NHxe2x80x94CH2CH2Nxe2x80x94(CH2)zxe2x80x94H and wherein Y is S, m is 0 and n is 1-4.
According to another embodiment the compound has the general structural formula: 
wherein R15 is selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, and (C1-C6)alkoxy and wherein R1-R5 are as described above.
According to yet another embodiment the compound has the general structural formula: 
wherein R12 is selected from the group consisting of xe2x80x94COxe2x80x94NHxe2x80x94CH2CH2NH2, xe2x80x94COxe2x80x94NHxe2x80x94CH2CH2Nxe2x80x94(CH2)zxe2x80x94H, and xe2x80x94COxe2x80x94N.(CH2)2NR15.(CH2)2 and wherein R1-R5 and R7-R10 are as described above. Preferably, Y is S, m is 0 and n is 1-4. In a more preferred embodiment m is 0 and n is 1-4. In another preferred embodiment Y is S, wherein R1, R2, R3, R4, R5, R7, R8, R9, and R10, are H, and wherein R6 is selected from the group consisting of xe2x80x94COxe2x80x94NHxe2x80x94CH2CH2NH2 and substituted or unsubstituted xe2x80x94CO-piperazine, the substituents selected from the group consisting of xe2x80x94H, halogen, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, and (C1-C6)alkoxy.
A pharmaceutical composition is provided according to another aspect of the invention. The pharmaceutical composition includes a pharmaceutically acceptable carrier and a compound of the invention, as described above, in an amount effective to inhibit calcium channels. In one embodiment the pharmaceutical composition also includes a medicament other than the compound for the treatment of a disorder associated with calcium channel activity. Disorders associated with calcium channel activity include, for example, cardiovascular disease, pulmonary hypertension, peripheral vascular disorder, migraine disorder, mania, epilepsy, depression, hyperuricemia, and asthma (achalasia asthma and bronchial asthma). In one embodiment the medicament for the treatment of cardiovascular disease is a medicament for the treatment of hypertension. In another embodiment the medicament for the treatment of cardiovascular disease is a medicament for the treatment of congestive heart failure. In yet another embodiment the medicament for the treatment of cardiovascular disease is a medicament for the treatment of angina.
According to another aspect of the invention an intermediate in the preparation of the compounds of the invention is provided. The intermediate compound has the general structural formula: 
wherein R1, R2, R3, R4, and R5, independent of one another, are selected from the group consisting of hydrogen, halogen, nitro, alkyl, alkoxy or piperonyl.
A method for inhibiting calcium channel activity is provided according to another aspect of the invention. The method involves the step of contacting a cell having a calcium channel with a compound of the invention, as defined above, in an amount effective to inhibit calcium channels.
In another aspect the invention is a method of treating a subject having a disorder associated with calcium channel activity by administering to the subject a compound of the invention, as defined above, in an amount effective to inhibit calcium channels in the subject and a pharmaceutically acceptable carrier. Disorders associated with calcium channel activity include, for example, cardiovascular disease, pulmonary hypertension, peripheral vascular disorder, migraine disorder, mania, epilepsy, depression, hyperuricemia, and asthma (achalasia asthma and bronchial asthma). In one embodiment the subject has a cardiovascular disease. In a preferred embodiment the cardiovascular disease is selected form the group consisting of hypertension, congestive heart failure, arrhythmia, and angina. In other embodiments the subject has a disorder selected from the group consisting of pulmonary hypertension, peripheral vascular disorder, migraine disorder, mania, epilepsy, depression, hyperuricemia, and asthma (achalasia asthma and bronchial asthma).
In one embodiment the method includes the step of administering a medicament other than the compound for the treatment of cardiovascular disease. Preferably the medicament is for treating hypertension. A medicament for treating hypertension in one embodiment is a medicament selected from the group consisting of Ajmaline; xcex3-Aminobutyric acid; Alfuzosin Hydrochloride; Alipamide; Althiazide; Amiquinsin Hydrochloride; Amlodipine Besylate; Amlodipine Maleate; Amosulalol; Anaritide Acetate; Aryloxypropanolamine derivatives; Atiprosin Maleate; Belfosdil; Bemitradine; Bendacalol Mesylate; Bendroflumethiazide; Benzothiadiazine derivatives; Benzrhiazide; Betaxolol Hydrochloride; Bethanidine Sulfate; Bevantolol Hydrochloride; Biclodil Hydrochloride; Bisoprolol; Bisoprolol Fumarate; Bucindolol Hydrochloride; Bupicomide; Bufeniode; Bufuralol; Buthiazide: Candoxatril; Candoxatrilat; Captopril; N-Carboxyalkyl derivatives; Carvedilol; Ceronapril; Chlorothiazide Sodium; Chlorthalidone; Cicletanine; Ciclasidomine; Cilazapril; Clonidine; Clonidine Hydrochloride; Clopamide; Cyclopenthiazide; Cyclothiazide; Cyptenamine tannates; Darodipine; Debrisoquin Sulfate; Delapril Hydrochloride; Diapamide; Diazoxide; Dilevalol Hydrochloride; Diltiazem Malate; Ditekiren; Doxazosin Mesylate; Ecadotril; Enalapril Maleate; Enalaprilat; Enalkiren; Endralazine Mesylate; Epithiazide; Eprosartan; Eprosartan Mesylate; Fenoldopam Mesylate; Flavodilol Maleate; Flordipine; Flosequinan; Fosinopril Sodium; Fosinoprilat; Guanabenz; Guanabenz Acetate; Guanacline Sulfate; Guanadrel Sulfate; Guanazodine; Guancydine; Guanethidine Monosulfate; Guanethidine Sulfate; Guanfacine Hydrochloride; Guanisoquin Sulfate; Guanoclor Sulfate; Guanoctine Hydrochloride; Guanoxabenz; Guanoxan Sulfate; Guanoxyfen Sulfate; Hydralazine Hydrochloride; Hydrazines and phthalazines; Hydralazine Polistirex; Hydroflumethiazide; Imidazole derivatives; Indacrinone; Indapamide; Indolapril Hydrochloride; Indoramin; Indoramin Hydrochloride; Indorenate Hydrochloride; Ketanserin; Labetalol; Lacidipine; Leniquinsin; Levcromakalim; Lisinopril; Lofexidine Hydrochloride; Losartan Potassium; Losulazine Hydrochloride; Mebutamate; Mecamylamine Hydrochloride; Medroxalol; Medroxalol Hydrochloride; Methalthiazide; Methyclothiazide; Methyldopa; Methyldopate Hydrochloride; Methyl 4 pyridyl ketone thiosernicarbarzone; Metipranolol; Metolazone; Metoprolol Funiarate; Metoprolol Succinate; Metyrosine; Minoxidil; Monatepil Maleate; Muzolimine; Nebivolol; Nitrendipine; Ofornine; Pargyline Hydrochloride; Pazoxide; Pelanserin Hydrochloride; Perindopril Erbumine; Pempidine; Piperoxan; primaperone; Protoveratrines; Raubasine; Rescimetol; Rilemenidene; Pronethalol; Phenoxybenzamine Hydrochloride; Pinacidil; Pivopril; Polythiazide; Prazosin Hydrochloride; Primidolol; Prizidilol Hydrochloride; Quaternary Ammonium Compounds; Quinazoline derivatives; Quinapril Hydrochloride; Quinaprilat; Quinazosin Hydrochloride; Quinelorane Hydrochloride; Quinpirole Hydrochloride; Quinuclium Bromide; Ramipril; Rauwolfia Serpentina; Reserpine; Saprisartan Potassium; Saralasin Acetate; Sodium Nitroprusside; Sotalol; Sulfinalol Hydrochloride; Sulfonamide derivatives; Tasosartan; Teludipine Hydrochloride; Temocapril Hydrochloride; Terazosin Hydrochloride; Terlakiren; Tiamenidine; Tiamenidine Hydrochloride; Ticrynafen; Tinabinol; Tiodazosin; Tipentosin Hydrochloride; Trichlormethiazide; Trimazosin Hydrochloride; Trimethaphan Carnsylate; Trimoxamine Hydrochloride; Tripamide; Tyrosinase; Urapidil; Xipamide; Zankiren Hydrochloride; and Zofenoprilat Arginine.
In another preferred embodiment the medicament is for treating congestive heart failure. In one embodiment the medicament for treating congestive heart failure is selected from the group consisting of thiazide diuretics, metolazone, furosemide, bumetanide, ethacrynic acid, aldosterone antagonists, trimterene, and amiloride.
In yet another preferred embodiment the medicament is for treating angina. In one embodiment the medicament for treating angina is selected from the group consisting of Acebutolol, Alprenolol. Amiodarone, Arotinolol, Atenolol, Bepridil, Bucumolol, Bufetolol, Bufuralol, Bunitrolol, Bupranolol, Carozolol, Carteolol, Celiprolol, Cinepazet Maleate, Diltiazem, Espanolol, Felodipine, Gallopamil, Imolamine, Indenolol, Isosorbide Dinitrate, Isadipine, Limaprost, Mepindolol, Molsidomine, Nadolol, Nicardipine, Nifedipine, Nifenalol, Nilvadipine, Nipradilol, Nisoldipine, Nitroglycerin, Oxprenolol, Oxyfedrine, Ozagrel, Penbutoolol, Pentaerythritol, Tetranitrate, Pindolol, Pronethalol, Propranolol, Sotaiol, Terodiline, Timolol, Toliprolol; Amlodipine Besylate; Amlodipine Maleate; Betaxolol Hydrochloride; Bevantolol Hydrochloride; Butoprozine Hydrochloride; Carvedilol; Cinepazet Maleate; Metoprolol Succinate; Molsidomine; Monatepil Maleate; Primidolol; Ranolazine Hydrochloride; Tosifen; Verapamil Hydrochloride; and Tirofiban Hydrochloride.
According to another preferred embodiment the medicament is for treating arrhythmia. In one embodiment the medicament for treating arrhythmia is selected from the group consisting of sodium channel blockers such as quinidine, procainamide, disopyramide, moricizine, lidocaine, mexiletine, phenytoin, tocainide, encainide, flecainide, propafenone, indecainide; b-adrenergic blockers, such as propranolol, acebutolol, esmolol; and compounds that prolong repolarization, such as amiodarone, bretylium, sotalol. Other antiarrhythmics include Acebutol, Acecaine, Adenosine, Ajmaline, Alprenolol, Amiodarone, Amoproxan, Aprindine, Arotinolol, Atenolol, Bevantolol, Bretylium Tosylate, Bubumolol, Bufetolol, Bunaftine, Bunitrolol, Bupranolol, Butidrine Hydrochloride, Butobendine, Capobenic Acid, Carazolol, Carteolol, Cifenline, Cloranolol, Gallopamil, Indenolol, Ipratropium Bromide, Lorajmine, Lorcainide, Meobentine, Metipranolol, Mexiletine, Nifenalol, Oxprenolol, Penbutolol, Pindolol, Pirmenol, Practolol, Prajmaline, Pronthalol, Pyrinoline, Quinidine Sulfate, Quinidine, Sotalol, Talinolol, Timolol, Tocainide, Verapamil, Viquidil and Xibenolol.
In one embodiment the administration is per oral. In another embodiment the administration is parenteral. In another embodiment the administration is intravenous.
In yet another aspect of the invention a kit is provided. The kit includes a package housing a container containing the compounds of the invention in an amount effective to inhibit calcium channels and a pharmaceutically acceptable carrier, and instructions for using the compound to treat a subject having a calcium channel blocking disorder.
In one embodiment the kit also includes a second container containing a medicament for the treatment of cardiovascular disease. In this embodiment the instructions are for using the compound and the medicament to treat cardiovascular disease. The medicament for the treatment of cardiovascular disease in some embodiment may be selected from the group consisting of a medicament for the treatment of hypertension, a medicament for the treatment of congestive heart failure, a medicament for the treatment of angina.
In another embodiment the kit also includes a second container containing a medicament for the treatment of a migraine disorder. In this embodiment the instructions are for using the compound and the medicament to treat the migraine disorder.
These and other aspects of the invention are described in greater detail below.